Data published to date clearly demonstrate good pharmaceutical perspectives of a new class of biologically active substances called mitochondria-addressed antioxidants (MAAs) (see Skulachev (2005) IUBMB Life., 57:305-10; Skulachev (2007) Biochemistry (Mosc)., 72:1385-96; Antonenko et al. (2008) Biochemistry (Mosc)., 73:1273-87; Skulachev et al. (2009) Biochim Biophys Acta., 1787:437-61; Smith et al. (2008) Ann. N.Y. Acad. Sci., 1147:105-11; see also WO2007046729, WO2009005386; U.S. Pat. No. 6,331,532; EP 1047701; EP 1534720; and Green (1974) Biochem. Biophys. Acta., 346:27-78).
The above-mentioned sources disclose the results of studies of MAAs under laboratory conditions in vitro or animal models. However, in order to use any compound as active pharmaceutical ingredient, the compound must meet certain requirements. For example, the compounds must comply fully with the national regulators requirements summarized in corresponding documents, pharmacopoeial monographs. The main requirements are: authenticity, impurity content, heavy metal content, water content, residual organic solvent content, sterility, method of quantitative measurement of the compound, methods of packaging, labeling and transportation.
Also, characteristics of the compound listed in regulatory documents as well as its pharmaceutical activity must remain within postulated limits during the postulated shelf storage time. Particular attention should be drawn to the total content of impurities, as well as the content of single impurities. In particular, single impurities which cannot be individually identified and fully characterized should not constitute a significant proportion (in most cases—more than 1%) of the total content of impurities.
Another significant difficulty with the practical applications of MAAs as pharmaceutical substances is that in the descriptions of inventions related to MAAs (see above), a large number of compounds claimed as mitochondria-addressed antioxidants have been disclosed, but they have different (sometimes even opposite) biological activity (for example, see Antonenko et al. (2008), Biochem. (Mosc), 73:1273-87). Thus, there is a need for the development of methods for design of biologically active substances with well-defined, predetermined properties suitable for the specific application of the compound. There is also a need of methods to predict properties and biological activity (and thus, clinical activity) of MAAs on the basis of Skulachev-ions.